The goal of our studies is to determine whether treatment of streptozotocin-induced diabetic rats, an animal model for Type I diabetes, or Zucker Diabetic Fatty (ZDF) rats, an animal model for Type II diabetes, with Enalapril, an angiotensin converting enzyme (ACE) inhibitor, or AVE7688, a vasopeptidase inhibitor, which inhibits both ACE and neutral endopeptidase activities, prevents and/or reverses the development/progression of diabetic neuropathy (DN). Treatment of diabetes patients with ACE inhibitors is a common form of treatment for renal and cardiovascular disease. However, there is a lack of knowledge about the potential benefits of ACE inhibitor treatment for DN. ACE inhibitors have been shown to have antioxidant and neuroprotective properties this provides a rationale for using these drugs in the treatment of DN. Our working hypothesis is that vascular dysfunction contributes significantly to the development/progression of DN. Previously we demonstrated that in epineurial arterioles of the sciatic nerve acetylcholine-mediated endothelium-dependent vascular relaxation is mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), whose biological identity is unknown. We also demonstrated that vascular tone is regulated by calcitonin gene-related peptide (CGRP) and that epineurial arterioles are innervated by sensory nerves containing CGRP. We have shown that diabetes alters the activity of each of these vasodilators causing decreased blood flow to the nerve. Based on preliminary studies we hypothesize the C-type natriuretic peptide (CNP) functions as EDHF in epineurial arterioles. CNP, a vasodilator, is metabolized by neutral endopeptidase and CNP activity/expression is decreased by diabetes. We propose that treating Type 1 and Type 2 diabetic rats with Enalapril or AVE 7688 will attenuate the development/progression of DN by: 1) preventing oxidative stress in vascular tissue thereby protecting the activity of NO, 2) preventing the loss of CNP and protecting its bioactivity, and 3) protecting sensory nerves and the availability and function of CGRP. We will also use cultured microvessel endothelial cells to examine the effect of hyperglycemia on CNP expression. If successful, these studies could provide a rationale for designing clinical studies to further test the efficacy of ACE inhibitor treatment in human DN.